Process for preparing amlodipine benzenesulphonate

ABSTRACT

The invention relates to a novel process of amalodipine benzenesulphonate of formula (I) by reacting a new 2-[/2-carboxy-benzoyl)-aminoethoxy/methyl/]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-di-hydropyridine derivative of general formula (II) wherein X represents hydrogen or alkali metal or alkali earth metal or quaternary ammonium—with benzenesulphonic acid.

The invention relates to a novel process for preparing amlodipinebenzenesulphonate (besylate) of formula

and pharmaceutical preparations containing the same.

According to the process disclosed in the invention the amlodipinebenzenesulphonate was prepared by reacting a novel phthalamidic acid{2-[/2-N-(2-carboxy-benzoyl)-aminoethoxy/-methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine}derivative of general formula

wherein X represents hydrogen or alkali metal or alkali earth metal orquaternary ammonium—with benzenesulphonic acid.

The invention relates also to the novel phthalamidic acid derivatives ofgeneral formula II—wherein X represents hydrogen or alkali metal oralkali earth metal or quaternary ammonium—per se and the process forproducing the same. These compounds are new final key intermediates(precursors) in the synthesis of amlodipine benzenesulphonate.

The invention relates also to a process for preparing a pharmaceuticalcomposition containing amlodipine benzenesulphonate when preparedaccording to the process of this invention.

Amlodipine{2-[(2-aminoethoxy)]-methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine}benzenesulphonate is a calcium channel blocking agent of a long durationof action, which is very useful in the treatment of ischaemic heartdisease and hypertension.

Amlodipine and the salts thereof were reported first in the EuropeanPatent Specification No. 89167 as one of the claimed novel1,4-dihydropyridines and pharmaceutically acceptable salts thereof. Ofthe different salts the maleate is disclosed as being particularlypreferred.

In the process according to the European Patent Specification No. 891671,4-dihydropyridines including amlodipine and the salts thereof areproduced from a precursor which can be the corresponding azidoderivatives being converted to the amino group by reduction, e.g. withtriphenylphosphine or zinc and hydrochloric acid or by hydrogenationover palladium catalyst. The disadvantage of this process is therelatively poor yield of the process for preparing the correspondingazide precursor, moreover the manipulation of azide compounds is lessconvenient due to the well-known explosiveness of the azidic structures.

Other precursor can be an amino-protected 1,4-dihydropyridine. In thesecases the amino 1,4-dihydropyridine including amalodipine can beobtained by removal of the protecting group, then the obtained1,4-dihydropyridine bases including amlodipine were isolated as an oil,and then were treated with acid.

In the case when the protecting group is benzyl, it is removed bycatalytic hydrogenation over palladium catalyst in a solvent such asmethanol at room temperature. When the protecting group is2,2,2-trichloroethoxycarbonyl, it is removed by reduction with zinc ineither formic or acetic acid.

In the case when the protecting group is phthaloyl, it can be removed byreaction with a primary amine, such as methylamine. The phthaloyl groupcan be removed also with hydrazine hydrate at reflux temperature in asolvent, such as ethanol. The phthaloyl group can be removed also withtwo equivalents of an alkali metal hydroxide, such as potassiumhydroxide at room temperature, followed by refluxing the mixture with anexcess of hydrochloric acid or sulphuric acid in tetrahydrofuran andwater solution.

The disadvantages of the above mentioned processes are in the relativelypoor yields of the processes due to the poor yields in the production ofthe 1,4-dihydropiridine precursors, whose preparation is carried out byHantzsch's synthesis of asymmetrical 1,4-dihydropyridine esters. Besideseach of the processes has technical, safety and environmental problems,too.

Namely, in the case of removing the phthaloyl group from the phthaloylamlodipine when methylamine is used the yield of the final maleate saltis low (49%) and the use of the harmful methylamine is required. Thisreagent is irritating to the eyes and to the respiratory organs (see:Merck-Index p 5944, 11. Ed., Merck and Co., Rahway, USA, 1989). Whenhydrazine hydrate is used the final amlodipine maleate salt was obtainedin a yield of 81%, however, the hydrazine is unambiguously carcinogenic(see: D. Beabei, Sicherheit, Handbuch f{dot over (u)}{dot over (r)}dasLabor, p. 136, GIT-Verlag, Darmstadt, 1991). When alkali metal hydroxideand hydrochloric acid is used the finally obtained amlodipine maleatesalt was described in a yield of 81%, however, the process can not bereproduced when followed the description of Example 22, Method C.

In the European Patent Specification No. 244 944 amlodipine besylate perse as a new chemical entity and pharmaceutical compositions containingthe same were claimed. Both the preparation of amlodipine besylate byreacting amlodipine base and benzenesulphonic acid and that of thepharmaceutical compositions containing the same by mixing the besylatesalt of amlodipine with a pharmaceutically acceptable diluent or carrierare also described and claimed, since amlodipine besylate is found to bemore advantageous over the previously described salts, e.g. maleatesalt, etc. because the previously described salts were not acceptablefor pharmaceutical formulation purposes.

The following two methods for the preparation of amlodipine besylate wasdescribed in the European Patent Specification No. 244 944.

In the first case amlodipine base was reacted with nearly stoichiometricamount of benzenesulphonic acid in a methanolic suspension and theamlodipine besylate was obtained in a yield of 83.8%. In the secondversion amlodipine base was reacted with ammonium benzene sulphonate inmethanol, then after a short heating under reflux the amlodipinebesylate was isolated in a yield of 70%.

In this patent specification the preparation of the starting amlodipinebase was not described.

The European Patent Specification No. 599 220 describes a process forthe preparation of amalodipine benzenesulphonate by reacting a noveltrityl-protected amlodipine base with benzenesulphonic acid in amethanolic or an aqueous methanolic medium at a temperature range from20° C. to the reflux temperature and then the amlodipinebenzenesulphonic acid was isolated and purified.

Although the aim of the above invention was to find a simple and easilyfeasible way which would afford the desired amlodipine benzenesulphonatein a high yield and high purity without supplementary preparation andisolation of amlodipine in a form of base as it was described in thepreviously mentioned two European patent specifications, the processdisclosed in this patent specification, however, has also somedisadvantages. Namely, the starting N-trityl-ethanolamine was producedin a rather complicated way which is very difficult to apply onindustrial scale. Besides the trityl-alkylating may be occurred both onthe amino and hydroxy group of the starting ethanolamine, consequentlyN-trityl, O-trityl and N,O-ditrityl-ethanolamine may be producedsimultaneously [see: J. G. Lammer, J. H. van Boom: Recueil Trav. Comm.Pays-Bas, 98(4), 243 (1979)]. Due to the acid lability of the tritylgroup the Hantzsch reaction can not be accomplished as desired. Theduration of the reaction between trityl-protected amlodipine base andbenzenesulphonic acid is rather long, i.e. the reaction mixture must bestirred for 13 hours. The product is obtained in a form of resin wherebythe processing thereof is extremely complicate including continuousextractions.

It has now unexpectedly been found that amlodipine benzenesulphonatesalt can be prepared directly without preparing amlodipine base,contrary to as described in the above European Patents Nos. 89 167 and244 944, by reacting an easily preparable, new, stable and purecrystalline phthalamidic acid derivative of general formula II—wherein Xrepresents hydrogen or alkali metal or alkali earth metal or quaternaryammonium—with benzenesulphonic acid in a one-step synthesis.

The amount of benzenesulphonic acid is at least a stoichiometric amountor a small excess of benzenesulphonic acid is to be used. The reactiontime is 3 to 4 hours.

The new phthalamidic acid derivatives of general formula II—wherein Xrepresents hydrogen or alkali metal or alkali earth metal or quaternaryammonium—can be prepared selectively by reacting4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-(2-phthalimidoethoxy)methyl-1,4-dihydropyridinewith a strong base. The thus obtained compound of general formulaII—wherein X represents alkali metal or alkali earth metal or quaternaryammonium group—can be isolated or without isolation, if desired, can bereacted with an acid to obtain phthalamidic acid derivative of generalformula II, wherein X represents hydrogen.

The starting material of this process can be obtained conventionally byHantzsch reaction.

Acceptable strong bases can be alkali metal hydroxides, e.g. potassiumhydroxide, sodium hydroxide, lithium hydroxide, etc., or alkali earthmetal oxides, e.g., calcium oxide, etc., or hydroxides or quaternaryammonium bases, e.g., tetramethylammonium hydroxide, etc.

The quantity of the strong bases is not decisive, however, practicallyat least a stoichiometric amount of strong base or more conveniently aslight excess of strong base is required.

For the neutralisation step a stoichiometric amount of acid according tothe applied base is required.

The reaction with a strong base is carried out at room temperature andthe neutralisation step with the acid is carried out during ice-cooling.

The invention is described in more detail as follows.

In the process according to the invention the new phthalamidic acid orits basic salt of general formula II—wherein X represents hydrogen oralkali metal or alkali earth metal or quaternary ammonium—was reactedwith at least a stoichiometric amount of the aqueous solution ofbenzenesulphonic acid under inert atmosphere, conveniently undernitrogen or argon in a mixture of an organic solvent and water,conveniently in a 2:1 mixture of water and acetonitril under heating.The reaction temperature amounts to 70-80° C. and the reaction time isabout 3 to 4 hours. The amlodipine benzenesulphonate of the formula Ican be obtained in a good yield (80-90%) and in a high purity (>99.5% byHPLC).

The advantages of the process according to the present invention can besummarized as follows.

1. The new phthalamidic acid derivatives which are new key intermediatesin the synthesis of amlodipine benzenesulphonate are obtainedselectively and in a pure crystalline form. Consequently the amlodipinebenzenesulphonate is prepared also in high purity from the new purecrystalline phthalamidic acid derivative.

2. The overall yield of the process for the production of amlodipinebenzenesulphonate via the new phthalamidic acid derivatives is muchhigher than that of the prior art, since the isolation of the amlodipinebase is avoided.

3. The whole working procedure of the present invention is essentiallyshorter and more simple than those described in the prior art.

4. The process of the present invention is easily applicable onindustrial scale.

5. The fact that the final intermediates of the process according to theinvention are obtained selectively and are isolated in a purecrystalline form is highly favourable for the purposes of the GoodManufacturing Practice which is essential for an active pharmaceuticalingredient.

6. The use of hydrazine or methyl amine, which reagents are harmful tothe health and to the environment can be avoided, because nodeprotection of the amino group is needed.

The following examples illustrate the process according to the inventionwithout limitation.

EXAMPLE 1 Amlodipine Benzenesulphonate

2-[/2-N-(2-carboxy-benzoyl)-aminoethoxy/methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine(3.9 g) was suspended in a mixture of water (100 ml) and acetonitrile(60 ml) under argon at room temperature and benzenesulphonic acid (1.2 g) in a solution of water (20 ml) was added to the suspension. Thereaction mixture was stirred at 80° C. for 3 to 4 hours. Then thesolvent was evaporated and the product was crystallised by cooling, thenfiltered and washed with water. The title product (3.5 g; 87%) wasobtained, which was recrystallised from a mixture of ethyl acetate andmethanol.

Melting point: 200-204° C.; TLC (Kieselgel, Merck 5719), R_(f): 0.31(pyridine/acetic acid/water/ethylacetate 16/5/9/70).

EXAMPLE 2 Amlodipine Benzenesulphonate

2-[/2-N-(2-carboxy-benzoyl)-aminoethoxy/methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinesodium salt (5.8 g) was suspended under argon in a mixture of distilledwater (120 ml) and acetonitrile (70 ml), then benzenesulphonic acid (3.5g) in a solution of distilled water (20 ml) was added to the mixture.The reaction mixture was stirred for 3 to 4 hours at 70-80° C. Afterevaporation of the solvent the title compound (5.5 g) was crystallisedby cooling. The title compound was recrystallised from ethanol to give4.5 g (80%) of the purified product.

EXAMPLE 32-[/2-N-(2-Carboxy-benzoyl)-aminoethoxy/methyl]-4-(2-chlorophenyl)-3-ethoxy-carbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine(Formula II, wherein X represents hydrogen)

a.) Preparation With Potassium Hydroxide

4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[(2-phthalimido-ethoxy)-methyl]-1,4-dihydropyridine(10.8 g) was suspended in isopropanol (80 ml), then a solution ofpotassium hydroxide (1.6 g) in water (40 ml) was added to the suspensionwith stirring at room temperature under nitrogen for 3 to 4 hours.During ice-cooling 1 N hydrochloric acid solution (28 ml) was added andthe precipitated product was filtered and washed with water. The titlecompound (10.9 g, 98%) was obtained, melting point: 167-169° C.

TLC (Kieselgel) R_(f): 0.29 (benzene/methanol 14/3).

1H NMR CHARACTERIZATION

Instrument: Varian UNITYINOVA 500 (500 MHz for 1H) [D6] DMSO as solvent,TMS as internal standard; (30° C.).

δ: 1.10 t (3H, OCH2CH3); 2.22 s (3H, CH3); 3.43-3.48 m (2H, OCH2-CH2NH);3.50 s (3H, OCH3); 3.56-3.65 m (2H) (2H, OCH2-CH2NH); 3.92-4.10 m (2H)[OCH2CH3]; 4.58 d (1H) and 4.67 d (1H) [—CH2O—]; 5.31 s (1H) [CH]; 7.11td (1H), 7.21 td (1H), 7.26 dd (1H), 7.34 dd (1H), 7.42 dd (1H), 7.51 td(1H), 7.57 td (1H), 7.78 dd (1H) [ArH]; 8.41 t (1H) & 8.43 s (1H)[2×NH]; 12.90 br s (1H) [COOH].

b.) Preparation With Sodium Hydroxide

4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[(2-phthalimidoethoxy)-methyl]-1,4-dihydropyridine(6.5 g) was suspended in isopropanol (20 ml) at room temperature underargon, then 1N sodium hydroxide solution was added to the suspension.The reaction mixture was stirred at room temperature for 3 to 4 hours.After evaporation of the isopropanol the residue was cooled in ice and1N hydrochloric acid solution was added. The obtained title compound(6.4 g, 96%) was obtained, melting point: 165.5-166° C.

c.) Preparation With Lithium Hydroxide

4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[(2-phthalimido-ethoxy)-methyl]-1,4-dihydropyridine(2.7 g) was suspended in isopropanol (20 ml) at room temperature underargon, then a solution of lithium hydroxide (0.4 g) in water (20 ml) wasadded to the suspension. The reaction mixture was stirred at roomtemperature for 2 to 3 hours. After evaporation of the isopropanol itwas cooled in ice and 1N hydrochloric acid solution was added. The titlecompound (2.6 g, 93%) was obtained, melting point: 165.5-166° C.

b.) Preparation With Calcium Oxide

4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[(2-phthalimido-ethoxy)-methyl]-1,4-dihydropyridine(3.0 g) was dissolved in a mixture of tetrahydrofuran (30 ml) and water(20 ml) and calcium oxide (0.31 g) was added to the mixture withstirring. The reaction mixture was stirred for 1 hour at roomtemperature, then it was cooled in ice and 1N hydrochloric acid solutionwas added. After evaporation of the tetrahydrofuran the crystallineproduct was filtered and washed with water. The title compound (3.0 g,97%) was obtained, melting point: 165.5-166° C.

c.) Preparation With Tetramethylammonium Hydroxide

4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[(2-phthalimido-ethoxy)-methyl]-1,4-dihydropyridine(3.0 g) was dissolved in tetrahydrofuran (30 ml) and 25%tetramethylammonium hydroxide (4.0 ml) in water was added to thereaction mixture, which was stirred for 1 hour at room temperature. Thenthe reaction mixture was acidified with 2N hydrochloric acid solution (6ml). After evaporation of the tetrahydrofuran in vacuo the residue wascrystallised with diethyl ether to afford the title compound (3.0 g;97%), melting point: 165-166° C.

EXAMPLE 42-[12-N-(2-Carboxy-benzoyl)-aminoethoxy/methyl]4-(2-chlorophenyl)-3-ethoxy-carbonyl-5-methoxycarbonyl-6-methyl-1,4-DihydropyridineSodium Salt

4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[(2-phthalimido-ethoxy)-methyl]-1,4-dihydropyridine(6.5 g was suspended in isopropanol (20 ml) at room temperature underargon, then 1N sodium hydroxide solution (20 ml) was added. The reactionmixture was stirred for 3 to 4 hours at room temperature. A cleansolution was formed. The solvent was evaporated and the oily residue wascrystallised from water, filtered, washed with water to give the titlecompound (6.9 g), melting point: 140-146° C.

TLC (Kieselgel) Rf: 0.72 (pyridine, acetic acid, water, ethyl acetate16/5/9/70).

EXAMPLE 5 Formulation of Tablets Containing Amlodipine Benzenesulphonate

Anhydrous calcium hydrogenphoshate (315 g) and microcrystallinecellulose (525 g, 90 μm) are combined and transferred into a drum. Thenamlodipine benzenesulphonate (70 g) and microcrystalline cellulose(187.5 g, 50 μm) are combined and passed through a screen into the drumcontaining the above powder mixture. The screen used in the previousstep is rinsed with microcrystalline cellulose (525 g, 90 μm). Anhydrouscalcium hydrogenphosphate (315 g) was added to the mixture and the wholemixture was blended for 10 minutes. Then sodium starch glycolate (40 g)was added to the mixture followed by blending for 6 minutes. Finallymagnesium stearate (20 g) was added and the resulting mixture wasblended for 3 minutes. The powder mixture was then pressed into tabletsby conventional methods.

This method was used to make tablets containing different concentrationsof the amlodipine benzenesulphonate salt.

What is claimed is:
 1. A process for the preparation of a compound offormula (I)

which comprises the step of reacting a compound of the formula (II)

wherein X is hydrogen or alkali metal or alkaline earth metal orquaternary ammonium—with benzensulphonic acid.
 2. A process according toclaim 1, characterized in that the compound of the formula II is reactedwith at least a stoichiometric amount of benzensulphonic acid.
 3. Aprocess according to claim 1, characterized in that the reaction wascarried our in an inert solvent at an elevated temperature.
 4. Acompound of the formula (II)

wherein X is hydrogen or alkali metal or alkaline earth metal orquaternary ammonium. 5.2-[/2-N-(2-carboxy-benzoyl)-aminoethoxy/methyl]-4-(2-chlorophenyl)-3-ethoxy-carbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine.6. Process for the preparation of a compound of formula II—wherein X ishydrogen or alkali metal or alkaline earth metal or quaternary ammoniumwhich comprises the step of reacting4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2(2-phthalimidoethoxy)methyl-1,4-dihydropyridinewith a strong base, and if desired, reacting the obtained compound offormula II—wherein X is alkali metal or alkaline earth metal orquaternary ammonium—with or without isolation with an acid to obtain thecompound of the formula (II) where X is hydrogen.
 7. Process accordingto claim 6, characterized in that the strong base is alkali metalhydroxide, alkaline earth metal oxide or hydroxide, or quaternaryammonium base.
 8. Process according to claim 7, characterized in thatthe strong base is used in at least a stoichiometric amount of the4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2(2-phthalimidoethoxy)methyl-1,4-dihydropyridineto obtain the compound of the formula (II) wherein X is alkali metal,alkaline earth metal or ammonium and, if desired, neutralizing saidcompound of formula (II) with a stoichiometric amount of acid to obtaina compound of the formula (II) wherein X is hydrogen.
 9. Processaccording to claim 7 characterized in that the reaction with the strongbase is carried out at room temperature and the reaction with the acidis carried out during ice-cooling.
 10. A process according to claim 6which further comprises the step of reacting the compound of the Formula(II) with benzene sulphonic acid to obtain amlodipine benzenesulphonate.